Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes
Shahmoradian, Sarah H.; Lewis, Amanda J.; Genoud, Christel; Hench, Jürgen; Moors, Tim E.; Navarro, Paula P.; Castaño-Díez, Daniel; Schweighauser, Gabriel; Graff-Meyer, Alexandra; Goldie, Kenneth N.; Sütterlin, Rosmarie; Huisman, Evelien; Ingrassia, Angela; Gier, Yvonne de; Rozemuller, Annemieke J.M.; Wang, Jing; Paepe, Anne De; Erny, Johannes; Staempfli, Andreas; Hoernschemeyer, Joerg; Großerüschkamp, Frederik; Niedieker, Daniel; El-Mashtoly, Samir F.; Quadri, Marialuisa; Van IJcken, Wilfred F.J.; Bonifati, Vincenzo; Gerwert, Klaus; Bohrmann, Bernd; Frank, Stephan; Britschgi, Markus; Stahlberg, Henning; Van de Berg, Wilma D.J.; Lauer, Matthias E.
(2019) Nature Neuroscience, volume 22, issue 7, pp. 1099 - 1109
(Article)
Abstract
Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and
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electron microscopy and tomography on postmortem human brain tissue from Parkinson’s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein–lipid compartmentalization not previously described in the Parkinsons’ disease brain.
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Keywords: General Neuroscience
ISSN: 1097-6256
Publisher: Nature Publishing Group
(Peer reviewed)